Menopause & Obesity

The speakers answered delegate questions offline. Here are their answers:

Q1: Does age of puberty onset interact with age of menopause, i.e. does menopause occur earlier in women who experienced an earlier puberty? If so, it would be interesting to see how this relationship is affected or not by excess adiposity.
A1, Prof George Mastorakos: The accepted concept is that the age of puberty has nothing to do with the age of menopause, based on epidemiological observational data. The physiopathologic explanation for this is unclear.

Q2: Why is it that individuals with anorexia don't experience excess fat tissue accumulation, despite having hormonal profiles similar to those of menopausal women?
A2, Prof George Mastorakos: It is true that in anorexia estrogens are low and sometimes lower than those in early menopause. However, the orexigenic stimulus resulting from the absence of estrogens does not suffice to overcome the steady impulse of those women to not eat which is driven by higher CNS centers. Of note, although this pathology is called anorexia, these women express appetite and sometimes even a strong one which they suppress experiencing thus, a positive feeling.

Q3: Are your data on menopause limited to women who have obesity and pregnancy? What about the women with obesity who have undergone hormone therapy and identify as another gender?
A3, Prof Rossella Nappi: No, the data I have shown come from a longitudinal cohort and there are no information on the link of menopause/overweight and obesity and parity. I am not aware of data specifically conducted in transgender population with regards to menopause and obesity but this is a very interesting topic of research.

Transcripts are auto generated, if you spot an error, please email enquiries@easo.org

Hey, let's get started. I will introduce the session quickly. My name is Lisa, I'm representing the European Association for the Study of Obesity.

Welcome to today's EASO Collaborating Centres for Obesity Management BOMS Network webinar, which focuses on obesity and menopause. I will just quickly give you the rules and I'll hand over to our session chair today, who is Dr. Andrea Cidden, the co-chair of the EASO Obesity Management Working Group. So today's session is recorded.

You should have received a notification when you entered the call, so if you would like to watch the session back after, please do, or share it with your colleagues. We'll have around 45 minutes of expert presentation and that will be followed by a Q&A with our expert speakers. So if you would like to ask a question, please do use the chat section.

It's not a separate Q&A, it's just the chat section we're going to be using for questions. Lastly, your feedback is very, very valuable to us. So when you leave today's webinar, you will see a feedback survey.

Please complete this because it really helps inform the future schedule for these COMS webinars and it helps us understand what kind of topics you would like to see and learn more about. If you would like to follow EASO on social media, please do. There's a Twitter account and a Facebook page.

I will add the links into the chat. But that's it from me. I will pass over to our expert chair, Dr. Andrea Cudin, to introduce the session and the speakers.

Thanks a lot. Thank you. Thank you very much, Lisa, for the presentation and these important messages on housekeeping.

Thank you, everybody, for joining us today. We have a very interesting topic, menopause and obesity strategies for care and management, and very good speakers to talk about. First, pathophysiology of menopause and obesity by Professor Rossella Nappi, which is Professor of Obstetrics and Gynecology, President-elect of the International Menopause Society, Chief of the Research Center of Reproductive Medicine and Director of the Gynecological Endocrinology and Menopause Unit at San Mateo Foundation of University of Pavia, Italy.

And then, after we learn about the pathophysiology, we learn how to manage the obesity during menopause, and the talk will be given by Professor George Mastorakos, I'm sorry, Professor of Endocrinology at the National and Kapodistrian University of Athens, Faculty of Medicine, Greece. And then we'll have 15 minutes of Q&A and sharing some time with you and the speakers. So, Professor Nappi, the floor is yours.

Thank you, dear. I really appreciate the invitation, and I found in this webinar an older friend of when I was a junior researcher, and I welcome everybody to my lecture. What happened here? Here we are.

Sorry. So, you will think why an OBGYN has an interest in obesity, especially regarding menopause. But this is because the first reason is that really obesity is a gender issue, and it's an ongoing pandemic nowadays, as you know very well, and we really need to help women in a diverse world in order to contract this specific condition that is so crucial for every step of woman life, but in particular for reproduction.

And we always think about reproduction in connection with weight gain or weight loss for many different reasons from adolescence to menopause. But we really need to be convinced that being a woman is a non-modifiable risk factor for obesity, because the reproductive milestones, they may play a role. And the way we handle reproductive milestones in terms of consequence, as we will focus our attention on the menopause, this will be relevant for the birth of the condition.

There are some things we cannot change, for example, our genes or the age, but the way we handle this reproductive transition really seems to be critical, and we will see it. And also, we have to consider that menopause may affect other aspects related to modifiable factors, such as, for example, the way women perceive stress, the way they diet, the way they practice physical activity, and the amount of medication they may need to overcome that particular moment in their life. Think about the use of antidepressants, for example, they have a crucial role in weight control.

So, at the end of the day, menopause is very, very important. And we know that weight control is one of the main concerns of post-menopausal women. This is a survey I conducted with a Polish friend many years ago, in which when we asked two large set of women in the age range between 55 and 65 what about they believe is more relevant for their health at menopause, weight control is really on the top of the list, and more than six out of ten women reported the importance of this topic, even more than cancer or heart disease or bone health, all different conditions very much associated with menopause.

And indeed, when we asked this same sample of women which one is the symptom you experience in your menopausal period, on the top of the list we have hot flashes, that is the very common symptom that women they usually report more or less in 78 out of 10 women around the time of menopause and beyond, but one out of two women they say gaining weight is very much relevant, and I had this experience. So, this is the reason why OB-GYN and reproductive medicine in menopause clinic they have to keep an eye on this condition. And with this in mind, with a couple of friends, especially Santiago Palacios in Spain, this is a colleague of mine working in the menopause field since many years, we have recently overviewed all the different domains that relate obesity and menopause, and I will touch upon some of this in order to point your attention to the relationship between the way menopause affects the fat mass, the way also obesity and overweight affect menopause.

I will share with you some information on some controversial data on the effect of obesity on age at menopause, and we will focus more on the effect of obesity on vasomotor symptoms, touching a little bit the relationship of obesity, osteoporosis and fracture risk, the so-called obesity paradigm, and effect of obesity on other specific parameters of the menopause. And then I will give the floor to Giorgia to introduce the way we handle obesity at the time of menopause and the choices we may have also in terms of menopause hormone therapy for these women. Let's start with the concept that weight gain per se cannot be attributed to the menopause transition, and we know this from a study that was conducted in North America.

I don't know if you are aware there is this cohort of women in North America from different ethnicities, and this cohort gives us a lot of information in a longitudinal study. So, in 2010 the authors they analysed what happened during the natural transition from pre-menopause to post-menopause in subsequent consultations. And you see from the graph that across the natural transition, change in menopause status was not significantly associated with development of obesity or severe obesity.

And it was extremely interesting to observe that when we compare women who underwent surgical menopause with women that were in the natural pre-menopausal or early perimenopausal period, these women they had a significant increase in the odds of obesity and an even higher increase around five with a confidence interval that was really between two and eleven of reporting severe obesity. So, entering menopause abruptly due to sudden ovarian exhaustion can lead to a significant amount of weight gain in menopausal women. It was interesting to observe also that African American and Hispanic women progressed more quickly to obesity across the natural transition, whereas Chinese and Japanese women progressed more slowly.

Results were similar for the severe obesity class and the only exception was that there were no difference in the cumulative incidence of obesity for Caucasian versus Hispanic. So, age is an important factor and another very important point is if obesity influences the reproductive hormone levels. So, the partner of release of FSH that you know is the hallmark of making a menopausal diagnosis from pre-menopause to the different stages of menopause.

We can go across the late pre-menopausal when women still have a menstrual cycle with a range no longer than seven days delay or seven days anticipation. Then we go into the early transition in which women they have menstrual irregularities even two, three months of amenorrhea, then late transition when there is a longer period of time between irregular bleeding, and then in the post-menopause when women they stop having their periods since at least 12 months. And you see it's interesting to observe that obesity is an important factor in hormone dynamics independent of age, race, and smoking in midlife of women.

And nowadays we still do not understand following so many years why this is the case. But you see very clearly that for example there is no difference in FSH level among different groups of BMI, so normal women, overweight, and obese across the transition. But when we are post-menopausal women with obesity they had lower level of FSH.

And interestingly enough these women they have a significantly higher level of estradiol during the post-menopausal period and this is completely at variance with what happened during pre-menopause. Indeed in pre-menopause it is interesting to observe that women they are in the normal weight range they have higher estradiol levels. And we can have many explanations that are easier during the post-menopause because we know that there is a conversion to estrogen from the peripheral tissue, the adipose tissue is converted to estradiol and this is extremely critical for oncological risk especially estrogen-dependent cancer.

You know very well endometrial cancer type 1 and even breast cancer and many other conditions they may be affected by erratic presence of estrogen without the anti-proliferative effect of progesterone that we see during the fertile age. Another very interesting point that we really need to study better is the association between BMI and the age at menopause. I believe you are aware that in general across the world menopause occurs usually between 45 and 55 years of age and is much less common to have premature menopause.

We know that one out of 100 women enter menopause before 40 and around 7-8% enter menopause in the age range between 41 and 45 and a minority enter menopause later on following the age of 55. When we look at the swine cohort the one I showed you before you see that there was no association between obesity and the age at natural menopause in North America in women of different ethnicity and that there was an association between surgical menopause and obesity. We saw that obese women they enter menopause early due to surgery and they gain also more body weight as I've shown you.

However, an international pool analysis of not so many prospective studies by the way supported a previously reported association between higher BMI and later menopause. If you think about you have more estrogen so you may bleed erratically. However, also another study pointing to the relationship between ovarian reserve and therefore reproductive aging not really menopause but that period of life in which women they still have bleeding but they are not fertile anymore so they enter a period that we may define fetipause so you do not conceive naturally and for example if you want to have a baby you should look for eggs donors in order to achieve your maternity project.

In this context of reproductive medicine research you see that this biomarker that we name antimicrobial hormone that is not a hormone that we measure to diagnose menopause but we really need measure to diagnose how many eggs are left for reproduction. You see that this biomarker is significantly lower in women with obesity than in those without obesity and BMI was negatively correlated with MH levels in all study population. There are many explanations about this concept and the most plausible is that the inflammatory condition associated with high BMI can induce an early aging of the ovarian tissue especially the granulosa cells they are so sensitive to low-grade inflammation and yet in a very recent study that's been suggested that lower MH7 levels during the menopausal transition could be indeed associated with higher markers of obesity especially the inflammatory ones and may be predictive of future obesity related cardiometabolic complications and this is very important nowadays and this is a huge topic of research in the menopause medicine setting because we really need to understand which ones are the women that will benefit more from preventive strategies at midlife and when we have erratic menstruation.

Why menopause is a turning point in metabolic health? This is a cartoon I produced from a beautiful review article that was out there in the literature quite recently which as we said there is no doubt that aging plays a role. Lifestyle changes are relevant because at this time of life we change the diet, the eating behavior and our attitudes to perform regular physical activity unless we are cancelled but it's very important to focus our attention on the hormone shifts at around the time of menopause and these hormone shifts is significantly associated to adipocyte dysfunction and very briefly because I'm sure that Jorge will explain you even better than me, when we have estrogen in our body this is a signal that is so crucial for reproduction we have hyperplasia of the tissue of the adipose tissue, we have a predominance of supracutaneous deposits and we have usually a more metabolically healthy function of the adipocytes with a certain amount of protection from developing insulin resistance and so we have a better insulin sensitivity whereas when we enter surgical menopause or natural menopause and we have a significant lack of estrogen in our body we start having also a hypertrophy of our adipose cells, we have much more visceral deposits, we have several inflammatory phenomenon into the adipose tissue and we enter a vicious circle that will lead to metabolically unhealthy people and developing diabetes, cardiovascular disease and in general metabolic disorders and this is a cartoon that is very dear to my heart because we recently published with some friends working in this field on the importance of looking at these multi-systemic changes related to estrogen decline at the time of menopause especially during the transition because at this time is really the moment in which we observe depending on the fluctuation and then on the early lack of estrogen that it's really the moment in which we have to focus because everything is occurring at this time. We increase the visceral fat and this will be associated with more general inflammation in the body that will lead to several processes affecting different domains of women's health including sedative stress and this is strongly related to insulin resistance as you know but this is also related at the time of menopause to developing hypertension and on the other way around the visceral effect is significantly associated with an increase of cholesterol, total cholesterol, LDL cholesterol and other biomarker of dyslipidemia, dysglycidemia and is associated with endothelial dysfunction that is significantly related to hypertension in a vicious circle and this is important because it's really the lack of estrogen but also the fluctuation of estrogen and we know that throughout genomic and non-genomic mechanism the relationship between reproduction and metabolism is really there.

It's so important during fertile life to optimize energies for reproduction during when you conceive a baby. We see a lot in infertility clinic think about polycystic ovarian syndrome associated with the metabolic phenotype but this is even more important during the pregnancy because estrogen affects the energy balance and even eating behavior and affect adipose tissue, the b-cell function survivor, insulin sensitivity and lipid homeostasis and energy homeostasis not only in the adipose tissue or the pancreatic islands but also in the liver, in the muscles and at multiple levels within the body. So to optimize this change is very very crucial and there is a significant shift in the body composition across the menopausal transition so it's not just a question of gaining weight but it's really a question of gaining kilos and fat mass around your waist.

You see this is always a longitudinal study that was published some years ago in which you recognize the different periods across the transition final menstrual period is time zero and then you observe the women before and the women after and you see the increase in waist circumference and in fat mass and this is significantly around the time of the last menstrual bleeding in the first especially in the first one two years after the menopause and there is an absolutely cumulative six year increase in fat mass of around 3.5 kilos and a six year decrease in skeletal muscle mass of around 0.23 kilogram and you gain more or less one centimeter per year in waist circumference and this is very important not only for the normal silhouette of women so for self-esteem and other very critical domain of quality of life for women around the time of menopause but as you know better than me this is very crucial for your metabolic health. Fat mass continues to increase but there is a slow increase after this early menopausal period and it's even more interesting that when you do regional fat distribution with a more sensitive technique for studying body composition it's important to remember that we of course we can measure the waist the hip in our patient but this is not enough because what is there around the menopausal transition it's really the increase of the visceral fat and this has been demonstrated very well so it's not yes the waist is increasing but there is an acceleration of the ratio between the visceral and the subcutaneous and so when we want to do some good research and practice in this context especially in Caucasian white patient we really need to use the DEXA or we really need to use a technique that help us to study better what is the tissue that it's really increased and when we do so and we put a lot of literature together so I really summarize in this cartoon it's crucial to observe that symptomatic women during the menopause and you remember the symptom more important hot flashes is there in a significant amount of women 80% we know that when these symptoms are persistent or moderate severe and these occur more or less in 30% of the women when you correlate from all the longitudinal studies a significant amount of variable not only the BMI per se or the waist circumference but you correlate also the lean body mass on the fat mass the reverse the insulin resistance the unfavorable LDL, HDL, cholesterol and other markers such as apolipoprotein A1, B triglyceride, other hemostatic and adipocaine profile think about leptin think about adiponectin and you consider hypertension as well and also the way women enter the menopause so in women they have an unchanged site length over the menopausal transitions such as occur in sudden surgical menopause for example all these parameters they are significantly more expressed in women having vasomotor symptoms so in our view in the menopause practice we really believe that reporting vasomotor symptoms with a significant impact on your quality of life repeated episodes during the day we calculate usually seven episodes per day or 35 episodes by a week especially two three during the nights that wake you up and as you know sleep is so essential for cardiometabolic health you will suffer more from cardiovascular risk in the future endothelial dysfunction, atherosclerosis, metabolic syndrome and cardiovascular disease in general so hot flashes are red flag for a risk to be in your patient and so you may predict the cluster of women they will suffer more this is a cartoon i like because it's very recent and was produced by a research fellow in endocrinology working in my department and she summarized the relevance of having obesity for another very important domain of female quality of life around the menopause and beyond that is female sexual dysfunction but in this cartoon you always may see a larger domain of women well-being they are always there even during the fertile age but they are much more relevant during post-menopause for example urinary incontinence a lot of comorbidities that women they may have obstructive sleep apnea and we may list even more to think about some osteoarthritis condition etc they may have an impact on quality of life they may have an impact also on different domain of the sexual response in women mainly poor arousal, low libido etc and also this cartoon is nice because it summarizes what we know already about the obesity condition these women they have a poor body image, low self-esteem, there is a lot of stigma as you know you are working so hard to counteract this stigma but this is something that is also related to menopause because we really need to remove the stigma from the menopausal condition and women they really need to be at this time of their life to cope with this natural transition and to try to feel better and to end my talk I want to share you a couple of data we have on the controversial issue of osteoporosis as you know very well we consider the bone mineral density in our working day in the menopause clinic because osteoporosis as a risk factor is significantly associated with estrogen deprivation and there was a common knowledge that post-menopausal women with obesity they do not suffer of these bone loss across their transitions and however we discovered very recently doing a lot of systematic review and analysis of court studies that women with obesity especially following menopause they are at higher risk of vertebral fracture we still don't know very well which one is the mechanism we named this condition the obesity paradigm I'm sure that in your association you study this very much but we don't have to give for granted that post-menopausal women with obesity they do not suffer from obesity and indeed the BMI as you know very well is included in our screener the FRAX that we use in daily practice so I would like to hand the microphone to George presenting one of my patients Linda she is 54 and you see she is suffering from obesity and she is gaining weight even more at the time of menopause this is the very simple workout we do in our clinic we measure the very simple metabolic risk factor we try always to collect this information to try to see how we can help this patient they already have a cardiometabolic risk out there and of course we work in in pairs with our colleagues in endocrinology our colleagues in nutrition medicine lifestyle medicine and we always start counseling women on losing weight and we do that with lifestyle medicine first nutrition and exercise and we counsel women on the importance of losing at least five ten percent of their body weight in order to improve remember not only all the condition that may be associated with the menopause especially the insulin resistance syndrome that we always screen that is so common in every overweight woman and it's pandemic in women with obesity but most importantly to counsel them to relieve hot flashes and other menopausal symptoms because there are plenty of data suggesting that this is the case and you have always to remember that we need to be careful in prescribing menopause hormone therapy to women with obesity because according to the most recent guideline a BMI higher than 30 is considered a condition which the risks generally overweight the benefits why because women they are already obese they may be at risk of thrombosis for example but it's important to remember that transdermal estradiol may be considered especially now that we have more possibilities to combine with also natural progesterone and we have plenty of data out here suggesting that the bioidentical hormones the traditional one the one they are studied in clinical trial not the compounded one they may be safely used in obese women women with obesity unless other significant cardiovascular or thrombotic risk factors are there and with this I invite you all to the 19th world congress on the menopause and in October in Australia if you want to be with us also for a holiday I welcome you all as a president or elector of the international menopause society thanks a lot for your attention and I'm ready to take your question. Thank you, thank you very much we are a little bit late and for the interest of time we'll move to the next talk of Professor Masorakos and hopefully we'll have time to answer one quick question in the end if not Lisa maybe we can collect the questions that will be written on the chat and try to answer them after that so please Professor Masorakos the floor is yours thank you.

Thank you very much after this wonderful introduction into the issues regarding menopause and obesity thank you Andrea for introducing me and I'll try to use a red pen in order to show some points regarding my slides. I was advised to divide my talk to these parts like consideration for managing obesity in menopause crisscrossing with other health conditions and then in yellow the holistic approach to obesity management in menopause together if we have time with a case study similar to that one presented by Professor Nappi. I will go very quickly over issues which have been very nicely touched already by Professor Nappi and so everybody now knows that during the future years women are going to spend more and more time in menopause so at some time maybe in the next 50 or 100 years women are going to stay more in menopause than in their hormonal period of life for example today 95 percent of women arrives at menopause and over 50 percent at the age of 75 whereas the life expectancy is more than 40 years in western countries for women reaching menopause.

Just to remind you we have already since about 2010 used this kind of presenting the pre-menopausal and the post-menopausal period of time which includes the menopausal transition and this refers to years which change from woman to woman and you can see that this straw representation includes the changes in menstrual cycles and the changes in important hormones markers such as FSH levels we're eventually going to use it. So how do we have in menopause which might be related directly with the development of obesity rapid hypostrogenemia eventually unhealthy nutrition and low physical activity we'll see how this is influenced by the decrease of insurgents and as already very nicely mentioned the increase and redistribution of fat mass from gyno due to abdominal obesity regarding us clinicians the use of waist circumference as a marker and waist to hip ratio it can be very very helpful in order to distinguish this redistribution of course if we have possibility to have access to DEXA scans then that would be the best. With and without estrogens already mentioned that estrogens are very very important because they especially regarding the subcutaneous fat we usually tend to call it the good fat tend to decrease lipogenesis and increase lipolysis eventually through the epinephrine effect and the other point I would like to mention is that as far as it has to do with the central nervous system the estrogens decrease feed consumption and they increase activity and energy expenditure this is very interesting estrogens are going kind of inducing women to expend more energy and actually it's just taking a look on the famous Krebs cycle which produces the energy now all the cells of our body by production of ATP you see that all stages of this pathway are influenced positively by estrogens so when we ovariectomize rats like you have with the full black rectangles then you see their weight going up but if you give them estradiol in the gray circles you see that you can reverse this phenomenon but not only that also you can reverse the phenomenon of developing insulin resistance and what says insulin resistance insulin resistance means hyperinsulinemia increase of insulin so when to these ovariectomized rats you substitute the lack of estrogens by estrogen administration this hyperinsulinemia goes down so again estrogens help to decrease insulin resistance.

Regarding their role in the central nervous system estradiol plays a very important role having to do with the hypothalamus here you see the lateral part of the hypothalamus this triangular form which is right is juxtaposed to the third ventricle and you see how estradiol affects all these famous nuclei such as the paraventricular nuclei the dorsal medial the ventromedial and so forth but also the arcuate nucleus where you have major molecules as you all know since you're so much interested in obesity and having to do with appetite the molecules having to do with g-carotene py a gooty related peptide the interesting thing is that estrogen acts as a powerful anorexigenic agent on the human body although both obese and unobese menopause groups had relatively equal estradiol concentrations suggesting as a professor Napier already mentioned the potential effect of other factors having to do with energy homeostasis and there comes the lifestyle and the daily dietary intake. I was advised to introduce certain aspects having to do with other areas of health in our body and as an endocrinologist I chose to refer to the role of menopause related obesity with other hormones such as insulin, leptin, cortisol and thyroid hormones taken as examples and just starting with insulin you can see that this time having to do with visceral obesity not subcutaneous obesity you see that estradiol blocks lipolysis from visceral obesity through its er alpha receptor and then it decreases the levels of free fatty acids and so by decreasing the levels of free fatty acids decreases the development of insulin resistance at the level of the liver. Without estradiol all these phenomena are reversed and here we are with the development of insulin resistance already mentioned.

What is insulin resistance means and how does it work through the adipose tissue particularly the visceral adipose tissue? You have seen already nice adipose tissue cells the yellow ones but as you have seen in the previous pictures you have these smalls here which increase in number and these cells are macrophages. Macrophages are related to inflammation so when the visceral obesity is increased inflammation goes up. What is the marker for inflammation? C-reactive related protein and there you see that the more the trunk fat increases the more CRP goes up and the straight line has to do with the correlation in male whereas the dotted line in female and you see that in menopause this correlation in females starts to get the same slope as in males and this again goes with the redistribution of the fat and the transformation of the pear-shaped obesity in women to apple-shaped obesity in menopausal women and when you try to correlate this CRP a wonderful marker of the development of adiposity together with the metabolic syndrome you see that this marker rather correlates with the androidal fat mass and we know that the more CRP the more the features of the metabolic syndrome increase from one up to five the more the CRP goes up so here we have to correlate the metabolism of the changed metabolism in menopausal women who becomes a person with obesity towards the development of metabolic syndrome and indeed here you see how women in menopause who have normal BMI excessive BMI and women have metabolic syndrome they tend to have more insulin so hyperinsulinemia and c-peptide so it's clear that insulin resistance develops together with increasing increase of their leptin levels a clear marker of the increase of adiposity but this goes as well in parallel with the development of molecules clearly related to inflammation such as the pro-inflammatory cytokine interleukin-6 and PIA-1.

Does this help us to understand the involvement of inflammation with insulin resistance? Of course because here we have one of the explanations for the acquired insulin resistance since the pro-inflammatory cytokines all three here mentioned TNF-alpha IL-6 and interleukin-1 beta they stop the production of the receptors GLUT4 which help glucose to get into the cells so if glucose does not get into the cells a relative hyperglycemia is going to be produced which is going to result to hyperinsulinemia meaning insulin resistance and the same equally these three molecules influence a wrong transmission of the message of insulin through its receptor in the interior of the cell so clearly obesity means insulin resistance but does it mean insulin resistance only? No. We know now that in postmenopausal women together with increase of age there is hyperlipidemia observed which has to do with the decrease of the number of leptin receptors showing that there is a relative leptin resistance developed in the body of these women and is this important? It is because leptin as we know is one of the best ways to inhibit appetite and one of the best ways to stop getting more energy in their body. Is cortisol involved in this situation? Yes it is.

How this can be represented in this talk? Here you have a person who suffers endogenous hypercortisolism we all know this is called Cushing syndrome with the development of visceral adiposity and the famous buffalo hump and also other characteristics having to do with the red face and so on but here you have another person which is not quite different from the previous one because here again we see that there is visceral obesity there is a buffalo hump and this is simple obesity. Why does this woman with simple obesity in which terms resemble to a woman with endogenous hypercortisolism? This is because through life we suffer, Professor Nappi clearly stated this in the beginning of her talk, we suffer consecutive stress events which relatively draw our adrenals to bigger size and in this way they respond more and more. We lost the connection.

Are you okay now? I think it's okay for me. Can you still hear? Can you hear me? Yes. Okay so I turned off my video so I have a better signal in case this was the problem.

So these engrossed adrenals they produce more eagerly cortisol during the stressful events of life and why and we all know how cortisol can influence the development of visceral fat and not only that we have all shown many many years ago the relationships of the pro-inflammatory cytokines regarding the stimulation of the hypothalamic pituitary adrenal axis for the production of cortisol and as we have shown already the macrophages of the adipose tissue can produce these pro-inflammatory cytokines which will lead these women not only suffering obesity but at the same time having their own HPA axis, hypothalamic pituitary adrenal axis, stimulated to produce a relative hypercortisolemia. On top of that it is well known that people which reach a certain age, of course this is above the possible age, however this starts earlier, they show having a greater amount of cortisol. On the top you have the representation of older women having to do with younger women and you see that through the day there is a clear hypercortilisemia in these persons and this has been associated with decrease of the neurons in their hippocampi, the famous nuclei in the central nervous system.

So the more urinary cortisol these persons have the less the number of their neurons is there and this is well known now that cortisol is destructive for the neurons of the hippocampus and is this important for the regulation of hypothalamic pituitary adrenal axis? Very important because hippocampus plays an inhibitory role on the activity of the HPA axis. So the more we grow through age the more our hippocampus loses neurons and thus the more cortisol is produced. So these women they find themselves also at the very moment of their aging period where not only the macrophages of their adipose tissue through pro-inflammatory cytokines produces more cortisol but at the same time the destructive effect of cortisol on their neurons from their hippocampus produces more cortisol again.

On top of that leptin resistance and leptin is clearly shown to inhibit the HPA axis again. So you see that we have many reasons which associate and increase a relative increase of cortisol in these women which drives again the increase of visceral adipose tissue. I'm sorry we are four minutes left so do you think that you could summarize a little bit? Okay, thank you.

I'm going ahead very quickly. Thyroid hormones it's clear that we have hyperthyroid and hypothyroid states which are associated with the climacteric period and then just to talk about how we process with these women definitely we have to assess risk factors regarding their health and then we'll discuss the way we're going to treat these women. When we have to do with the lower levels of increased BMI between 25 and 27 then we can go with diet, physical activity and behavioral change.

If we go up then we start thinking about pharmacotherapy and Professor Nappi already mentioned how we have to be very careful regarding the administration of estradiol. The nutritional interventions I am very prone to suggest a Mediterranean diet is very beneficial and a recent nice review by Goncalves et al has summarized the effect of seven studies in menopausal women of the efficiency of nutrition. I will go over this.

The exercise is important however after 24 months we have not to overestimate its effect because you see that the exercise per se alone cannot produce loss of body weight in those women. However it is very important for decreasing visceral fat as you can see here and this is very important especially when a resistance exercise is associated with nutritional intervention and resistance exercise is very important because it increases the global physical capacity of these women. The effect of exercise is important in increasing muscular mass and decreasing visceral fat mass which as we have seen is important to induce and only older studies regarding CBT cognitive behavioral therapy have shown an important change only in 16 weeks only by using CBT almost seven percent of body weight in those women so this has not to be neglected and could be useful one and then the pharmaceutical agents I would think that hormone therapy could be helpful which has been shown in animals very efficiently but not that efficiently in women however it is clear that fat and here you can see again how the total abdominal fat goes down and total subcutaneous fat goes down when women are in hormone replacement therapy by estrogens and in those women you see that we have a change of the slope of the relationship between their body mass index and their interleukin-6 showing that the administration of estrogens to those women decreases their inflammatory status and this has been also shown in the famous WHO study in 2002 showing the decrease of hyperinsulinemia which is very important as a marker for the decrease of insulin resistance.

We can use anti-insulin resistant drugs such as metformin and pioglitazone we can use gastrointestinal lipase inhibitors such as Olistat and of course GLP analogs and others to come in the future. When should we use pharmacotherapy obese patients with a BMI over 30 overweight patients with a BMI of over 27 but with other related risk factors and when patients are unable to achieve weight loss despite their best use of lifestyle approaches to diet physical activity and behavioral changes and when patients weight stabilize before their goal weight is attained. So to summarize this and I will go over my case study in which I would like to outline and to exemplify the usefulness of estrogen replacement therapy together with the use of metformin in order to decrease the insulin resistance.

I would say we should actively challenge the obesogenic environment which englobes us all. We should all try to change dietary habits and help these patients and build physical activity into daily routines even before menopause. This is very important.

So the fight against the menopausal obesity starts much earlier I would say even in adolescence. Establish lifelong habits for nutrition physical activity and we should prescribe exercise. This is something which has to do in our everyday practice and advice for hormone therapy according to the suggestions of Professor Nappi already very well described when appropriate appropriate and properly administrated where for the patches and of course we protect uterus by prescribing progesterone and I would say micronized progesterone.

Thank you for listening. Thank you very much for these very interesting talks and really necessary for women and not just for them. For the interest of time we'll collect the questions.

I think Lisa that there are three or four relevant questions so we'll be answering them and then in the next days you'll have the answers. So thank you all very much for joining us today and we are looking forward to see you in the next webinar and in the next days in Venice during the European Congress of Obesity. So see you soon.

Goodbye. Thank you very much Andrea. Thank you.

Thank you. Thank you. Bye everybody.

Bye. Bye everyone. Thank you.

Thanks for your questions. Bye bye. Thanks.